INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2017
·Vol. 18
·期 4
·815
·
IF 3.226
Zhaojun Li,Hui Huang,Lili Huang,Lianfang Du,Ying Sun,Yourong Duan
In general, atherosclerosis is considered to be a form of chronic inflammation. Dexamethasone has anti-inflammatory effects in atherosclerosis, but it was not considered for long-term administration on account of a poor pharmacokinetic profile and adverse side effects. Nanoparticles in which drugs can be dissolved, encapsulated, entrapped or chemically attached to the particle surface have abilities to incorporate dexamethasone and to be used as controlled or targeted drug delivery system. Long circulatory polymeric nanoparticles present as an assisting approach for controlled and targeted release of the encapsulated drug at the atherosclerotic site. Polymeric nanoparticles combined with ultrasound (US) are widely applied in cancer treatment due to their time applications, low cost, simplicity, and safety. However, there are few studies on atherosclerosis treatment using polymeric nanoparticles combined with US. In this study, targeted dexamethasone acetate (DA)-loaded poly (lactide-glycolide)-polyethylene glycol-cRGD (PLGA-PEG-cRGD) nanoparticles (DA-PLGA-PEG-cRGD NPs) were prepared by the emulsion-evaporation method using cRGD modified PLGA-PEG polymeric materials (PLGA-PEG-cRGD) prepared as the carrier. The average particle size of DA-PLGA-PEG-cRGD NPs was 221.6 ± 0.9 nm. Morphology of the nanoparticles was spherical and uniformly dispersed. In addition, the DA released profiles suggested that ultrasound could promote drug release from the nanocarriers and accelerate the rate of release. In vitro, the cellular uptake process of fluorescein isothiocyanate (FITC)@DA-PLGA-PEG-cRGD NPs combined with US into the damaged human umbilical vein endothelial cells (HUVECs) indicated that US promoted rapid intracellular uptake of[email protected]PLGA-PEG-cRGD NPs. The cell viability of DA-PLGA-PEG-cRGD NPs combined with US reached 91.9% ± 0.2%, which demonstrated that DA-PLGA-PEG-cRGD NPs combined with US had a positive therapeutic effect on damaged HUVECs. Overall, DA-PLGA-PEG-cRGD NPs in combination with US may provide a promising drug delivery system to enhance the therapeutic effects of these chemotherapeutics at the cellular level.Keywords:dexamethasone acetate;polymeric nanoparticles;ultrasound;atherosclerosis;polypeptide targeting
研究领域:
药学
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心血管病学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-21
·
IF 10.6
Fei Yao,Cao Danping,Li Yanna,Wang Zhixiong,Dong Runyu,Zhu Menglin,Gao Peng,Wang Xiaoming,Cai Juan,Zuo Xueliang
Introduction Cisplatin-based chemotherapy is one of the fundamental therapeutic modalities for gastric cancer (GC). Chemoresistance to cisplatin is a great clinical challenge, and its underlying mechanisms remain poorly understood. Circular RNAs (circRNAs) are involved in the pathophysiology of multiple human malignancies. Methods High-throughput sequencing was performed to determine the differentially expressed profile of circRNA in GC tissues and cisplatin-resistant GC cells. Quantitative real-time polymerase chain reaction and Fluorescence in situ hybridization was utilized to confirm the dysregulation of circ_0008315 in GC tissues. To evaluate the prognostic significance of circ_0008315 in GC, we used Kaplan-Meier plot. The self-renewal ability of drug-resistant GC cell was verified through tumor sphere formation assay. GC organoids were constructed to simulate the tumor microenvironment and verified the function of circ_0008315 in cisplatin resistance of gastric cancer. In vivo evaluation was conducted using patient-derived xenograft models. Dual-luciferase reporter gene, RNA immunoprecipitation and miRNA pull-down assays were employed to investigate the molecular mechanisms of circ_0008315 in GC. Results We revealed that a novel circRNA hsa_circ_0008315 was upregulated in GC and cisplatin-resistant GC cells. Elevated circ_0008315 was also observed in cisplatin-resistant GC organoid model. High circ_0008315 expression predicted unfavorable survival outcome in GC patients. Downregulation of circ_0008315 expression inhibited proliferation, mobility, and epithelial-mesenchymal transition of GC cells in vitro and in vivo. Reducing circ_0008315 expression in cisplatin-resistant GC organoid model reversed cisplatin resistance. Mechanistically, circ_0008315 modulated the stem cell properties of GC through the miR-3666/CPEB4 signaling pathway, thereby promoting cisplatin resistance and GC malignant progression. Furthermore, we developed PLGA-PEG nanoparticles targeting circ_0008315, and the nanoparticles could effectively inhibit GC proliferation and cisplatin resistance. Conclusion Circ_0008315 exacerbates GC progression and cisplatin resistance, and can be used as a prognostic predictor. Circ_0008315 may function as a promising nanotherapeutic target for GC treatment. Graphical Abstract
研究领域:
肿瘤学
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分子生物学
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药理学
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纳米技术
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PubMed
高影响因子
AAPS PHARMSCITECH
·
2023
·Vol. 24
·期 8
·1-12
·
IF 3.3
Jiang Wenjing,Gao Xiangjun,Wang Qiuli,Chen Yang,Li Dan,Zhang Xiaoyan,Yang Xinggang
The existing exenatide microspheres have the problem of burst release in the early stage, and minimal release in the middle stage which makes it difficult to achieve effective blood drug concentration (platform period). In this study, the modified exenatide microspheres were constructed to address the aforementioned issues. Poly(D,L-lactic-co-glycolic acid) (PLGA) and triblock copolymer with sol-gel conversion characteristics (PLGA-PEG-PLGA gel) were introduced as carriers to prepare microspheres. The hot gel characteristics and hydrophilicity of PLGA-PEG-PLGA gel were utilized to decline the burst release and shorten the platform period. Simultaneously, zinc acetate and exenatide were combined to generate an insoluble complex to further reduce the burst release. Herein, we prepared three types of exenatide microspheres using the solvent evaporation method and investigated their characterization as well as in vitro and in vivo release. According to the experimental findings, the modified exenatide microspheres, i.e., PLGA-PEG-PLGA gel and PLGA co-loaded zinc-exenatide insoluble complex microspheres (Zn-EXT-Gel-MS), had smooth and rounded surfaces, with a particle size of 24.7 μm, and the encapsulation rate reached 89.43%. And it was released for 40 days in vitro , behaving better than the other two microspheres in terms of release behavior. When this product was administered subcutaneously to rats, it produced a comparatively constant plasma exenatide concentration that lasted for 24 days and superior bioavailability than the exenatide microspheres (EXT-MS). The creation of modified exenatide microspheres may serve as a heuristic method for other long-acting medications. Graphical Abstract Schematic diagram of the synthesis process and release curves of three types of exenatide microspheres in vitro and in vivo
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高影响因子
MOLECULAR PHARMACEUTICS
·
2017
·
IF 4.44
Yiyue Wang,Jing Li,Jing Jing Chen,Xuan Gao,Zun Huang,Qi Shen
The polylactic-co-glycolic acid polyethylene glycol conjugated with cell penetrating peptide R7 (PLGA–PEG-R7)/polysulfadimethoxine-folate nanoparticles loaded with docetaxel (DTX) and GDC0941 (R7/PSD-Fol NPs) were prepared to overcome multidrug resistance (MDR) and enhance the antitumor activity. First, polysulfadimethoxine-folate was synthesized to construct the R7/PSD-Fol NPs. The R7/PSD-Fol NPs were prepared with the abilities of effective entrapment and drug loading. Due to the pH-sensitive effect of PSD-folate, the releasing of DTX and GDC0941 from the R7/PSD-Fol NPs was lower in pH 7.4 buffer solution than that in pH 5.0 buffer solution. The half maximal inhibitory concentration (IC50) of MCF-7 and resistant to doxorubicin (MCF-7/Adr) cells illustrated the cytotoxicity of R7/PSD-Fol nanoparticles by using the MTT method. The uptake of R7/PSD-Fol NPs was visualized by using the fluorescence of Rh-123 to detect the targeting effect of folate on the surface of R7/PSD-Fol NPs. The results of the cell apoptosis and the depolarization of mitochondrial membrane potential (MMP) were adopted to show the cytotoxicity of the R7/PSD-Fol NPs on MCF-7/Adr cells. The Western blot revealed the inhibition of PI3K/Akt pathway in MCF-7/Adr cells induced by R7/PSD-Fol NPs. Finally, both in vivo distribution and in vivo antitumor showed the R7/PSD-Fol NPs displayed the better distribution at tumor site and the stronger suppression of tumor growth in the tumor bearing nude mice compared with control group. It was concluded that R7/PSD-Fol NPs loaded with DTX and GDC0941 could overcome MDR and enhance the antitumor effect further.
研究领域:
药理学
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肿瘤学
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纳米技术
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分子生物学
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PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2021
·
IF 3.738
Xiufen Du,Daquan Tan,Yang Gong,Yifan Zhang,Jiangyuan Han,Wei Lv,Tao Xie,Pu He,Zongjie Hou,Kun Xu,Jiying Tan,Bingdong Zhu
Protein-based subunit vaccine against tuberculosis (TB) is regarded as safer but with lower immunogenicity . To investigate effective adjuvant to improve the immunogenicity of TB subunit vaccine, we modified ploy(I:C) onto PLGA-PEG copolymer nanoparticle with polydopamine to produce a new nanoparticle adjuvant named “PLGA-PEG-poly(I:C)” (NP). M. tuberculosis fusion proteins Mtb10.4-HspX and ESAT-6-Rv2626c (M4) were encapsulated in the nanoparticles to produce the NP/M4 subunit vaccine. The PLGA-PEG/M4 nanoparticle was 200.21 ± 1.07 nm in diameter, and the polydispersity index (PDI) was 0.127 ± 0.02. Following modification with poly(I:C) by polydopamine, the NP/M4 was administered to C57BL/6 female mice intranasally and the immune responses were evaluated. The NP/M4 significantly induced antigen-specific CD4 + T cells proliferation, IL-2 and IFN-γ production. In addition, the NP/M4 could promote the production of antigen-specific IgG, IgG1 , IgG2c in serum, and sIgA in lung washings . Overall, our results indicated that the NP would be a potential TB subunit vaccine adjuvant with the ability to induce strong Th1-type cell-mediated immunity and humoral immune responses .
研究领域:
免疫学
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疫苗学
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纳米技术
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结核病
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DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2026
·
IF 6.9
Yuan Hao,Zhang Bingwen,Sun Wen,Liu Haofan,Hu Liandong
In this study, celecoxib (CXB) microspheres (CM) and ropivacaine (RPV) microspheres (RM) were prepared respectively. A poly (D, L-lactide-co-glycolide)-block-poly (ethylene glycol)-block-poly (D, L-lactide-co-glycolide) (PLGA–PEG–PLGA, PPP) was synthesized by copolymerizing glycolide and lactide with polyethylene glycol. CM, RM, and hydroxyapatite (HA) were then incorporated into PPP solution to construct the microsphere–hydrogel system (CRMH hydrogels). CM, RM, and CRMH were systematically characterized in terms of morphology, physicochemical properties, pH-buffering capacity, and degradation behavior. The pH-dependent drug release and release kinetics of the individual CM, RM and the CRMH hydrogels were also investigated. In vitro release studies demonstrated that CRMH hydrogels provided coordinated, sustained release of CXB and RPV at pH 6.2. In a rabbit osteoarthritis (OA) model, intra-articular (IA) administration of CRMH hydrogels achieved sustained drug retention and release within the joint cavity, and effectively promoted articular cartilage repair. Overall, the CRMH hydrogels showed promising synergistic therapeutic potential for OA.
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高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Li Yuan-Ce,Zhang Qi,Zhang Hong-Yang,Wang Yan-Wen,Sun Yu-Mei,Yang Bi-Juan,Yin Jun-Lin
Introduction: Artesunate, a derivative of artemisinin, has anti-malarial effects, and in recent years has also been reported to have anti-tumor activity. However, its anti-tumor mechanisms are not well understood. Methods: In this study, we focused on the targeting of Hsp90 by artesunate to inhibit tumor cell proliferation, which we examined using immunoprecipitation, a proliferation assay, flow cytometry, western blotting, a tumor xenograft animal model, and immunohistochemistry. Furthermore, to examine the tumor-suppressive effects of artesunatein nude mice, we used artesunate-loaded PLGA-PEG nanoparticles. Results: The binding of artesunate to Hsp90 was found to reduce the expression of its client proteins AKT, ERK, p-AKT, p-ERK, and EGFR, thereby blocking the cell cycle at the G0/G1 → S stage in lymphoma cells and inducing apoptosis. In addition, the results of tumor xenograft experiments revealed that artesunate reduced the expression of AKT and ERK proteins in tumor tissues, inhibited tumor proliferation, and reduced tumor size and weight. Furthermore, nanoparticle encapsulation was demonstrated to enhance the anti-cancer activity of artesunate. Discussion: We thus established that artesunate inhibits the proliferation of lymphoma cells by targeting the Hsp90 protein, and we accordingly believe that this compound has potential for development as a novelanti-tumor drug.
研究领域:
肿瘤学
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药理学
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分子生物学
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PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 3
·376
·
IF 5.5
Yuxing Zhang,Xixi Zou,Qiran Du,Xiaotao Dong,Uday Kumar Chinta,Ruyue Yu,Fei Wu,Tuo Jin
Objectives: Thermo-gelling hydrophilic polymers like PLGA–PEG–PLGA are known as injectable sustained-release depots for biologics, but they face challenges due to the occurrence of severe burst release. This study aimed to develop a strategy to avoid the initial burst release by pre-encapsulating proteins in polysaccharide microparticles through an aqueous–aqueous emulsion mechanism, thereby enhancing therapeutic retention and linear release kinetics.Methods: Five model proteins (G-CSF, GM-CSF, IGF-1, FVIII, BSA) were encapsulated in dextran microparticles, using an organic solvent-free aqueous–aqueous emulsion method. These particles were dispersed in a 23% (w/w) PLGA–PEG–PLGA solution and injected into a 37 °C release buffer to form a gel depot. The in vitro release profiles were quantified using ELISA and MicroBCA assays over 9–42 days. The bioactivity of the proteins was validated using cell proliferation assays (NFS-60, TF-1, MCF-7) and chromogenic kits. The in vivo pharmacokinetics of the FVIII-loaded formulations were evaluated in Sprague–Dawley rats (n = 5/group) over 28 days.Results: Protein-loaded dextran particles retained their structural integrity within the hydrogel and exhibited minimal burst release (≤5% within 30 min vs. >25% for free proteins). Sustained near-linear release profiles were observed for all the proteins, with complete release by day 9 (G-CSF, GM-CSF, BSA) or day 42 (FVIII). Rats administered with the thermal gel with FVIII–dextran particles showed a significantly lower peak plasma concentration (Cmax: 88.25 ± 30.21 vs. 132.63 ± 66.67 ng/mL) and prolonged therapeutic coverage (>18 days vs. 15 days) compared to those administered with the thermal gel with the FVIII solution. The bioactivity of the released proteins remained at ≥90% of the native forms.Conclusions: Pre-encapsulation in dextran microparticles effectively mitigates burst release from thermosensitive hydrogels, while preserving protein functionality.
研究领域:
药剂学
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生物医学工程
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药物递送系统
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蛋白质工程
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Zhen Wang,Bixi Ding,Yuanpei Zhao,Yue Han,Yu Sheng,Ling Tao,Xiangchun Shen,Jianping Zhou,Lei Jiang,Yang Ding
Increasing knowledge of drug delivery properties, tumor profiles and their relationship promotes precise administration regimens, representing a promising pattern to personalized tumor treatment. Herein, we propose a regulatory hydrogel depot toward metastatic cancer by establishing mathematical models between tumor characteristics and administration regimens. Specifically, a thermo-sensitive PLGA-PEG-PLGA polymer is introduced as injectable hydrogel matrix, of which the administration volume and frequency are manipulated elaborately according to tumor size and gel-degradation kinetics. Structurally, doxorubicin (Dox) and arginine-terminated nanoparticles containing KIAA1199 specific shRNA ( shKIAA RPDNs) are incorporated into hydrogels, thereby formulating a topical and sustained drug depot to achieve synergy treatment. For dual-targeting therapy, Dox interdicts DNA replication/transcription, and shKIAA persistently silences KIAA1199 protein to modulate aggressive phenotypes. After individual peritumoral injection, Gel/ shKIAA RPDNs/Dox demonstrates desirable distribution patterns and gel degradation kinetics with enhanced tumor penetration. Moreover, a preferable inhibition of tumor proliferation and metastasis is confirmed after twice treatment in 12 days, indicating better therapeutic efficacy with less dosage and frequency. Consequently, the controllable administration regimen inspired mathematical models of thermosensitive hydrogel provides an intelligent platform for personalized treatment to metastatic cancer.
研究领域:
肿瘤学
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药学
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生物医学工程
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分子生物学
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高影响因子
RSC Advances
·
2026
·Vol. 16
·期 23
·20895-20907
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IF 6.1
Xiaolong Xu,Yuze Zhou,Junhao Chen,Lujing Fei,Min Qi
The treatment of malignant melanoma, an aggressive skin cancer with high recurrence and metastatic potential, often presents challenges due to systemic toxicity and multidrug resistance in current therapies. In this study, we develop a localized therapeutic platform by integrating methotrexate–manganese (MTX–Mn) coordination nanoparticles into a thermosensitive PLGA–PEG–PLGA (PPP) hydrogel to achieve sustained and site-specific drug delivery for melanoma treatment. MTX–Mn nanoparticles were synthesized through coordination-driven self-assembly and comprehensively characterized by FTIR, 1H NMR, TEM, EDS, and zeta potential analyses, confirming successful coordination and uniform nanoscale features. In vitro experiments demonstrated that MTX–Mn significantly inhibited melanoma cell proliferation and migration. Flow cytometry further revealed that MTX–Mn induced pronounced G0/G1 cell-cycle arrest and effectively promoted apoptosis, which was confirmed by TUNEL staining. Mechanistic investigations indicated that MTX–Mn triggered severe mitochondrial dysfunction, including ultrastructural damage, elevated mitochondrial ROS generation, and collapse of mitochondrial membrane potential (JC-1), suggesting a mitochondria-associated antitumor mechanism. In vivo, peritumoral administration of PPP/MTX–Mn markedly suppressed tumor growth in a melanoma-bearing mouse model, reduced the tumor burden, and significantly decreased Ki-67 expression. Histological evaluation of major organs by H&E staining revealed no obvious pathological abnormalities, supporting good in vivo biosafety. Overall, this MTX–Mn-loaded thermosensitive hydrogel provides a promising strategy for effective and safe localized melanoma therapy.
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高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
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2023
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IF 5.4
Yan Zhu,Yanni Xu,Dong Han,Xiujin Zhang,Cheng Qin,Jing Liu,Lei Tian,Mengqi Xu,Yan Fang,Yang Zhang,Yabin Wang,Feng Cao
ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in atherosclerotic formation through mediated cholesterol efflux in macrophage-derived foam cells . In this study, a scavenger receptors AI (SR-AI) targeted theranostic nanoparticles was constructed for atherosclerosis regression via ABCA1 activation in foam cells. ABCA1-upregulator 5242331 and IR780 were encapsulated in PLGA-PEG micelles which were conjugated with SR-AI targeting peptide (PP1) to formulate the nanoparticles (SAU-NPs). Immunostaining revealed that SR-AI was highly expressed both in macrophage foam cells and in atherosclerotic plaque of ApoE −/− mice. The SAU-NPs have shown more active targeting to plaque lesion with higher stability compared with non-SR-AI targeted nanoparticles. The transformation from macrophage to foam cells was inhibited by SAU-NPs carried 5242331. Cholesterol deposition was effectively reduced in foam cells by SAU-NPs through activating the LXRα-ABCA1/ABCG1/SR-BI pathway. In conclusion, theranostic SAU-NPs which carried ABCA1-upregulator 5242331 exert beneficial effects on atherosclerosis regression via LXRα activation.
研究领域:
心脏病学
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纳米医学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2025
·Vol. 27
·期 10
·1-16
·
IF 2.6
Zhu Junqiao,Tang Wei,Sun Zhiting,Zhu Xinhai,Quan Qiang,Yin Jiaxin,Huang Qiugui,Jia Guoxia,Zhao Yang,Tang Yuqin,Zhang Yan,Xie Linhao,Zhao Jianfu
Multiple cycles of transarterial embolization chemotherapy for hepatocellular carcinoma (HCC) can easily cause the overexpression of P-glycoprotein (P-gp), leading to multidrug resistance (MDR) of HCC. Herein, we linked PLA (polylactic acid) with doxorubicin (DOX) through acid-sensitive hydrazone bonds to prepare PLA-ADH/DOX. Then, PLA-ADH/DOX and disulfiram (DSF) were physically encapsulated into PLGA-PEG (polylactic-co-glycolic acid-polyethylene glycol) as the backbone to fabricate a drug delivery system (DOX/DSF NPs) by nanoprecipitation and emulsion solvent evaporation method. The data of physicochemical characterization showed that DOX/DSF NPs enabled excellent stability at room temperature and pH sensitivity in an acidic environment. More importantly, DOX/DSF NPs could avoid P-gp-mediated efflux through endocytosis pathways and inhibit the function of P-gp by DSF, which increases cellular uptake of DOX in HepG2/DOX cells (hepatocellular DOX-resistant cancer cell line) and promotes DOX to enter the nucleus of HepG2/DOX cells for exerting the therapeutic effect in vitro. In addition, DOX/DSF NPs could increase intracellular reactive oxygen species (ROS) levels and reduce intracellular adenosine triphosphate (ATP) levels, thereby further inhibiting the function of P-gp, increasing intracellular concentration of drugs, and ultimately overcoming MDR in HCC. Hence, the combination of DOX and DSF delivered by DOX/DSF NPs with pH-sensitive and sequentially controlled drug release may provide a new way for MDR of HCC.
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高影响因子
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